Three Colorado studies show how tumors hijack the immune system to resist radiation therapy

More than a decade ago, radiation oncologists noticed a nifty
phenomenon: Sometimes radiation used locally against a tumor could excite the
immune system to attack cancer systemically throughout the body. It was as if the
use of radiation had somehow awoken the immune system to the presence of
cancer. Since then, a massive effort has been underway to harness this effect, hoping
to create this systemic anti-cancer activity with combinations of radiotherapy
and immunotherapy.

Unfortunately, “We’ve tried numerous combinations with
radiotherapy – triple therapy, different targeted strategies – and still we
cannot eradicate the tumors,” says Sana Karam, MD, PhD, investigator at CU Cancer Center and assistant
professor of Radiation Oncology at the CU School of Medicine.

What is driving this resistance to radiotherapy? In a new
study published in the Journal
of the National Cancer Institute, Karam and colleagues show that it may be
a special kind of immune cell called T-regulatory or Treg cells. Just as the
body has mechanisms to turn on the immune system, it also has ways to turn it
off, and Tregs are one of these ways, functioning like an ‘off’ switch that
keeps the immune system from running rampant through healthy tissues.

“Tregs are immunosuppressant cells that put the brakes on the
effector t cells. But Tregs also stop T cells from doing their job of killing
the cancer cell,” Karam says.

In this study, with first author Ayman
Oweida, PhD, radiation alone or Treg depletion alone wasn’t enough to kill head
and neck cancer models grown in mice, but together these two strategies
resulted in potent tumor reduction. The strategy makes sense: Radiation turned
on the immune system, and the depletion of Tregs ensured that cancer was not
able to turn it off.

“If you go at it just by taking away Tregs, there are no effector
T cells. You need something to inflame the environment, something to excite T
effector cells, and in this case that was the role of radiation,” Karam says.

Unfortunately, “We don’t have a good, safe agent that can eradicate
Tregs safely in humans. The way we’re doing it is a good way to understand the
biology, but it’s not a good strategy for patients,” Karam says.

Which is where the second line of research comes in. See,
independent of Karam’s work with radiation and Tregs is her work with a program
active in early embryonic development that many cancers restart to drive their
growth. Specifically, a “handshake” between EphB4 and ephrinB2 is essential for
neurogenesis in the developing brain, but previous work has shown that EphB4 and/or
ephrinB2 are upregulated in many cancers, including head and neck, and pancreatic
cancers.

“EphB4 has been studied not just in cancer, but in a lot of
diseases where the immune system is key. In cancer, we’ve shown that when you
inhibit the interaction between EphB4 and ephrinB2, you get a reduction in
tumor growth – and we’re opening a trial at CU Cancer Center with a drug that
inhibits EphB4-ephrinB2 interaction. But we also wanted to know why inhibiting this interaction acts
against tumors,” Karam says.

The group’s paper recently
published in the journal Cancer Research
with first author Shilpa Bhatia, PhD, shows that the most dramatic result of
stopping this communication between EphB4 and ephrinB2 is the reduction of
T-regulatory cells.

“It was total serendipity,” Karam says. “In this study, we really
had no plans to look at Tregs. A lot of studies have focused on activating the
T effector cells. But we found in our models, that when we stopped EphB4-ephrinB2
interaction, it wasn’t that we got more T effector cells, but that removing the
Treg suppressor cells all of the sudden made the T effector cells able to be
more active and do their work.”

“Both studies were going in parallel and we happened to have this
collision at the point of Tregs,” Karam says. “That’s the beauty of science,
you never know what you’re going to get.”

In a third study, published
in Clinical Cancer Research with
first author Shelby Lennon, BSc, the group tested ephrinB2 inhibition in models
of pancreatic cancer, where ephrinB2 expression has long been known to
correlate with poor prognosis. Collaborating with multiple collaborators including
Dr. Kirk Hansen in the CU Cancer Center Mass Spectrometry Shared Resource, the
group found that ephrinB2 inhibition resulted in less “fibrosis” in these
tumors, meaning that the tumors were packed less tightly with cross-linked
collagen fibers – like the twigs in a bird’s nest – which have been shown to
make pancreatic tumors less permeable to anti-cancer drugs, less vulnerable to
the immune system, and more likely to metastasize.

“What we saw was a significant reduction in fibrosis and a
remarkable reduction in disease burden,” Karam says.

Often, new anti-cancer drugs are built from the “bottom-up” or the
“top-down”: Either many drugs are tested against cells in hopes of discovering
a specific weakness; or scientists discover a specific weakness and design a
drug to exploit it. It’s as if the current studies happen to come at Tregs from
both directions. First, in a top-down approach that doesn’t necessarily depend
on knowing exactly how they work, the presence of Tregs seems to help cancers
resist radiotherapy; and second, in a bottom-up approach, it seems that
inhibition of the EphB4-ephrinB2 axis keeps these Tregs in check.

“It’s only when you really understand the basic biology, the
mechanisms of how things work, that you can develop rational therapeutics
against cancer,” Karam says.

Now with the understanding that Tregs create radiotherapy
resistance and that reducing EphB4-ephrinB2 can reduce Tregs, the group can
continue developing safe and effective drugs to target this mechanism of cancer
growth and resistance.